Technical Field
The present disclosure relates to compositions and methods for weight management and, more particularly, to Diels-Alder adducts of chalcone and prenylphenyl moieties, to oligomers of flavan-3-ol, or both, optionally in combination with other weight management agents, such as anorectic agents, a lipase inhibitors, cannabinoid receptor modulators, psychotropic agents, insulin sensitizers, stimulants, or satiety agents, as well as to methods of use thereof such as treating or preventing weight gain or obesity, promoting weight loss, appetite suppression, modifying satiety, or the like.
Description of the Related Art
Obesity is a food problem. In industrialized countries, affluence provides abundant and variable food items to the general public. Food, with the associated taste and olfactory pleasures, is an indulgence, not just for basic survival. As a result, obesity and obesity-related health issues are increasing rapidly and there is a strong need for dietary supplements that help with weight control. The market size for food supplements that decrease body weight is large and there are few effective products.
For many years, Cannabis sativa (marijuana) has been known to stimulate food consumption through the action of its active component, delta-9-tetrahydrocannabinol (THC), an exogenous cannabinoid. This effect prompted research into its mechanism of action. The binding sites for THC were eventually cloned and named CB1 and CB2. These receptors belong to the G-protein coupled family characterized by seven trans-membrane loop domains. Both receptors belong to Gi/0 subclass and signal by negatively regulating cyclic AMP levels. CB1 was also shown to activate potassium channels. CB2 receptor is present in immune cells and is not involved in regulation of food consumption. CB1, the cannabinoid receptor involved in feeding behavior, is widely expressed both in brain and peripheral tissues, including adipose tissue, skeletal muscles, liver, and gastrointestinal (GI) tract.
Most of the published CB1 receptor antagonists might be better termed “inverse agonists” as they are capable of inhibiting constitutive activity of non-occupied CB1 receptors. The major clinical indications for this group of compounds are obesity and substance abuse. In the past, five CB1 compounds have been tested in clinical studies. They include Rimonabant (Sanofi-Aventis, launched in 2006), MK-0364 (Merck, Phase III), Surinabant and AVE-1625 (Sanofi-Aventis, Phase II), and SLV-319 (Solvay, Phase II). Rimonabant (marketed as Acomplia®, Rimoslim™ or Zimulti®) was the first selective CB1 antagonist discovered in 1994. It was approved in 37 countries, but it has since been withdrawn from obesity treatment due to neurological side effects.
Another product on the market is tetrahydrolipstatin (orlistat, sold as Alli® or Xenical®). Orlistat was identified from a chemical library based on its inhibition of fatty acid synthase, but was developed as a pancreatic triglyceride lipase inhibitor. But, orlistat has been placed on a list of drugs having a potential signal of serious risk due to cases of liver toxicity, which has led to a change in the product labeling and the FDA is continuing to evaluate this issue to determine the need for any further regulatory action (see www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Surveillance/AdverseDrugEffe cts/ucm161063.htm).
From the foregoing, a need is apparent for improved compositions and methods for weight management.